The present invention relates to enzymatic processes for the resolution of enantiomeric mixtures of β-lactams useful in the preparation of taxanes.
The taxane family of terpenes, of which taxol and docetaxel are members, has attracted considerable interest in both the biological and chemical arts. Such taxanes may be prepared through a variety of semi-synthetic routes. In one, a β-lactam is coupled to a derivative of 10-deacetylbaccatin III to form a sidechain at the C-13 position of the derivative. As the stereochemistry of these taxanes may affect their pharmaceutical activity, methods allowing efficient stereospecific preparation of the intermediate β-lactam, as well as the final taxane products, have been the subject of investigation.
Brieva et al. (Brieva, R.; Crich, J. Z. and Sih, C. J., J. Org. Chem. 1993,58, 1068) reported that racemic β-lactam underwent selective kinetic hydrolysis with several Pseudomonas lipases and two penicillinases. Pseudomonas lipases used by Brieva et al. include P-30, AK and K-10.
Similarly, Patel reported in U.S. Pat. No. 5,879,929, that enantiomeric mixtures of certain β-lactams and, in particular, racemic mixtures of certain β-lactams, can be resolved by a stereoselective hydrolysis using a variety of lipases and enzymes. Lipases identified by Patel include Amano PS-30 (Pseudomonas cepacia), Amano GC-20 (Geotrichum candidum), Amano APF (Aspergillus niger), Amano AK (Pseudomonas sp.), Pseudomonas fluorescens lipase (Biocatalyst Ltd.), Amano Lipase P-30 (Pseudomonas sp.), Amano P (Pseudomonas fluorescens), Amano AY-30 (Candida cylindracea), Amano N (Rhizopus niveus), Amano R (Penicillium sp.), Amano FAP (Rhizopus oryzae), Amano AP-12 (Aspergillus niger), Amano MAP (Mucor meihei), Amano GC-4 (Geotrichum candidum), Sigma L-0382 and L-3126 (porcine pancrease), Lipase OF (Sepracor), Esterase 30,000 (Gist-Brocarde), KID Lipase (Gist-Brocarde), Lipase R (Rhizopus sp., Amano), Sigma L-3001 (Wheat germ), Sigma L-1754 (Candida cylindracea), Sigma L-0763 (Chromobacterium viscosum) and Amano K-30 (Aspergillus niger). Enzymes identified by Patel include enzymes derived from animal tissue such as esterase from pig liver, α-chymotrypsin and pancreatin from pancreas such as Porcine Pancreatic Lipase (Sigma). While these enzymes may be used in the stereoselective hydrolysis of β-lactams, the required purification of the enzyme can significantly increase the cost of the preparation of the β-lactam.
Whitesell et al. (Whitesell, J. K. Lawrence, R. M. Chimia, 1986, 40, 315) and Basavaiah et al. (Basavaiah, D. and Rao, P. Tetrahedron. Asym., 1994, 5, 223–234) reported successful application of pig liver acetone powder (PLAP), bovine liver acetone powder (BLAP) and chicken liver acetone powder (CLAP), in the resolution of numerous chiral secondary alcohols. Experimental evidence obtained to date, however, suggests that the use of these materials results in a product having relatively low optical purity. While the reason for this is not entirely clear, it is believed that this is the result of incomplete reaction rather than the enzyme's lack of selectivity which, in turn, is likely a consequence of inconsistent amounts of active enzyme present in different batches of the liver acetone powder.